TIP60 regulates PTEN expression, acetylation, and localization in cisplatin-resistant SCC

Non-melanoma skin cancers (NMSCs), including squamous cell carcinoma (SCC), remain highly prevalent, with global incidence rising each year. Cisplatin, a platinum-based chemotherapy drug, is commonly used to treat advanced SCC and several other cancers. Although many patients initially respond, intrinsic or acquired resistance frequently emerges, limiting its clinical efficacy. TIP60, a histone acetyltransferase that modifies both histone and non-histone substrates, plays key roles in DNA damage repair, cell-cycle progression, and apoptosis. Our research demonstrates that elevated TIP60 expression correlates with increased resistance to cisplatin in SCC cell lines. In contrast, the tumor-suppressor PTEN is essential for maintaining controlled cell growth and survival. Loss, decreased expression, or mislocalization of PTEN promotes drug resistance, proliferation, and enhanced cell survival across various cancer types. PTEN activity is regulated in part by acetylation and our lab has previously shown that ΔNp63alpha negatively regulates PTEN expression and activity. We hypothesize that TIP60 promotes resistance to cisplatin by suppressing PTEN expression, or modifying PTEN through acetylation, and altering its subcellular distribution. Consistent with this model, we found that PTEN levels were significantly reduced in cisplatin-resistant SCC cell lines compared with their cisplatin-sensitive counterparts. TIP60 knockdown in resistant cells increased PTEN transcript and protein levels, and enhanced PTEN promoter activity, supporting a transcriptional mechanism. TIP60 knockdown also reduced phosphorylated Akt levels, whereas TIP60 overexpression decreased PTEN and increased phosphorylated Akt. Subcellular fractionation demonstrated that TIP60 knockdown increased cytoplasmic PTEN in cisplatin-resistant cells. In addition, both TIP60 knockdown and pharmacological inhibition reduced PTEN acetylation, suggesting a post-translational mode of regulation. Together, these findings support a model in which TIP60 acetylates PTEN and negatively regulates its overall and cytoplasmic abundance, thereby enhancing pro-survival PI3K/Akt signaling and promoting cisplatin resistance. Defining the mechanisms underlying the TIP60-PTEN axis may uncover a novel therapeutic vulnerability to improve cisplatin effectiveness and support its continued use in SCC patients.